Medical dressing comprising an antimicrobial silver compound

ABSTRACT

A medical dressing comprising a complex of silver and being capable of releasing antimicrobial silver ion activity, the complex comprising silver ion, a transition element of Group IV of the periodic system of elements, cation, phosphate and hydrogen to enable a controlled release of silver ion activity to a wound bed.

This is a nationalization of PCT/DK02/00095 filed Feb. 8, 2002 andpublished in English.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a medical dressing comprising a complexof silver and being capable of releasing antimicrobial silver ionactivity to a wound, a method for preparing such dressing, and a methodfor treating a human being.

The antiseptic activity of silver compounds is a well-known property,which has been utilised for many years. The bacteriostatic andfungistatic effect is caused by the silver ion and a simple compound,which has been used clinically, is for instance silver nitrate. Silvernitrate in concentrations of 0.5-1% in water shows disinfectantproperties and is used for preventing infections in burns or forprophylaxis of neonatal conjunctivitis. For another silver compound,silver sulfadiazine, the antibacterial effect of the sulfadiazinemolecule is further enhanced by the complexing with the disinfectingsilver ion. In contrast to the silver nitrate, the solubility of thesilver sulfadiazine complex is low and hence, both of the two activeparts are only present in solution in low concentrations but may bepresent over a longer period of time before being washed out at site tobe treated. The silver sulfadiazine is intensively used in the treatmentof wounds, in particular burns, under the trademarks Silvadene® andFlamazine®. Silver-protein-combinations are yet other antisepticformulations, which have been used, in low concentrations as eye drops.

2. Description of the Related Art

Antiseptics based on the silver ion are further used in various medicaldevices. One example of such application is the use in the wounddressing sold by Johnson & Johnson under the trademark Actisorb® whichis an activated charcoal cloth dressing. Another example is the wounddressing sold under the trademark EZ-Derm by Genetic Laboratories whichdressing is a modified pigskin impregnated with a soluble silvercompound intended for treatment of burns.

A number of patents disclose compositions or devices showing antisepticproperties based on contents of silver compounds. EP 272 149 B1discloses a medical dressing of the ‘hydrocolloid’ type containing andreleasing active components. Silver chloride is a specificantiseptically acting compound mentioned in this patent.

EP patent publication No. 0 905 289 discloses antibacterial cellulosefibre being characterised in that a tertiary amine N-oxide was used as asolvent for pulp, and a silver based antibacterial agent selected fromthe group of silver zeolite, silver zirconium phosphate, silver calciumphosphate, and silver soluble glass. It is claimed that addingmagnetized mineral ore powder may increase the antibacterial effect.

A specific advantage in using the silver ion as antiseptic agent is thegeneral lack of formation of bacterial tolerance to the compound. Thisis in contrast to many types of antibiotics. However a major drawbackwhen using ionic silver for bacteriostatic purposes is the reduction ofthe ion to free silver, which results in dark staining.

In the treatment of chronic wounds it is desirable to have a productcapable of absorbing wound fluid and, at the same time also releasingantimicrobial activity to the wound bed. Burns, leg ulcers, diabeticfoot ulcers and pressure sores may have delayed or slowed healing due tocolonisation of the wound bed. For this purpose, it is desirable to havea dressing being able to absorb wound exudates and at the same timereleasing antimicrobial activity to the wound, to prevent infectionand/or delayed wound healing due to colonisation of the wound.

It is an object of the present invention to provide medical dressingscapable of rendering silver ions available sufficiently quickly and in asufficiently high and lasting concentration to ensure that an effectiveantiseptic activity is obtained and to ensure that the silver ions willnot be released unintendedly from the dressing.

Still further it is an object to provide a method for preparing suchmedical dressings without losing the antiseptic activity of the silverions.

Such medical dressings may e.g. be wound dressings, ostomy appliances ordressings for covering sites of the skin having an incision, e.g. for acatheter such as a catheter for drainage purposes.

It has surprisingly been found that certain silver complexes comprisingsilver and a transitional element of group IV of the Periodic System ofElements may be incorporated in an adhesive or foam matrix of a medicaldressing without loosing the antiseptic activity and that the release ofsilver ions may be controlled to ensure that silver ions will not bereleased from the dressing unintendedly and that the release may beinitiated in a controlled manner.

SUMMARY OF THE INVENTION

The present invention relates to a medical dressing comprising a complexof silver and being capable of releasing antimicrobial silver ion toe.g. a wound bed.

Furthermore, the invention relates to a method for preparing medicaldressings in the form of foam being capable of releasing antibacterialactivity to a wound bed.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is disclosed more in detail with reference to the drawingsin which

FIG. 1 shows a graphical representation of the release of silver indifferent media from a dressing according to the invention, and

FIG. 2 shows a graphical representation of the release of silver indifferent media from a dressing of the state of the art comprisingsilver.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a medical dressing comprising a complexof silver and being capable of releasing antimicrobial silver ionactivity, said complex comprising silver and a transitional element ofGroup IV of the Periodic System of Elements.

It has been found that silver is only released from a dressing accordingto the invention, when the dressing is contacted with a liquidcomprising ions and no release is seen when contacted with distilledwater. This effect is especially pronounced in connection with liquidspredominantly comprising monovalent ions.

This finding enables a controlled release of the silver ion activity inthat it is not released when a dressing is contacted with distilledwater, only on contact with an ionic solution. Thus, it is possible torinse e.g. a wound or a stoma or the peristomal area of the skin of anostomate or the area around an incision for e.g. drainage purposes usingdistilled water without risk of unintended early release of silver ionactivity before it is actually needed, namely when e.g. an exudate ispresent. Furthermore, silver ion activity is not released from parts ofa dressing not being wetted by an ionic solution. Still further,distilled water or essentially ion-free water may be used in theproduction and/or be incorporated in a product of the invention withoutreleasing the silver ion activity.

Without limiting the invention to any specific theory it is assumed thatan absorbent medical dressing is capable of absorbing exudate or thelike whereafter ion exchange with cations from the absorbed fluid in thedressing releases the silver promoting antimicrobial activity. Thus, itis assumed that when e.g. wound exudate is absorbed into a wounddressing according to the invention, an ion exchange between sodium ionsof the exudate and silver of the antimicrobial complex is initiated, andthe released silver ions will be transported into the wound bed toexercise antimicrobial activity.

The complex used in accordance with the present invention may preferablycomprise a transitional element such as titanium, zirconium or hafnium,and it is especially preferred that the silver is in the form of complexwith zirconium.

The complex is suitably a phosphate complex not having adverse effectwhen in contact with open wounds. Such complex preferably also comprisesa further cation such as an alkali metal ion e.g. lithium, sodium, orpotassium, preferably sodium.

A silver sodium hydrogen zirconium phosphate complex has proven to beespecially suitable for the purpose of the present invention.

The dressings of the invention may have a content of silver in the rangeof 0.01 to 30 mg silver/cm² wound dressing. The content of silver ispreferably in the range of 0.1 to 15 mg, more preferred in the range of0.2 to 6 mg, e.g. about 1 mg silver/cm².

It is preferred that a dressing of the invention comprises an absorbingconstituent or element and that the complex of silver is comprised insuch absorbing constituent or element as a wound exudate or other liquidwill then more easy come into contact with each other.

An absorbing constituent or element may preferably be a separate elementof an absorbing foam, a hydrogel, or paste, or be in the form ofhydrocolloids and/or an alginate in the form of a separate element orparticulate and homogeneously distributed in the dressing. In case of ahydrogel, care must be taken during production that no ionicconstituents are used in order not to release the silver ion activityfrom the complex of silver. Such hydrogels may thus comprise non-ionicabsorbers such as non-ionic cellulose derivatives, e.g. hydroxyethylcellulose or PVP and non-ionic water and optionally non-ionicpreservatives such as propylene glycol.

It has been found suitable that the absorption of a medical dressing ofthe invention is higher than 3 grams per gram wound dressing, preferablyhigher than 5 grams per gram wound dressing.

In a preferred embodiment of the invention, the dressing comprises apolyurethane foam layer forming at least a part of the skin-contactingsurface of the dressing. Such a foam may be produced incorporatingparticles of a complex comprising silver and a transitional element ofGroup IV of the Periodic System of Elements homogeneously distributed inthe foam without loosing the desired properties.

Such an absorbing element may in one embodiment constitute a dressing ofthe invention. In such case, the absorbing element may in itself showadhesive properties or it may not show adhesive properties and it willthen typically be secured to the desired site using conventional meanssuch as a cover dressing.

In a preferred embodiment of the invention, the dressing comprises askin-contacting surface comprising an area showing a skin friendlyadhesive.

Such a dressing may suitably be a dressing comprising a substantiallywater-impervious layer or film and a skin-friendly adhesive in which anabsorbing constituent or element is incorporated.

The skin-friendly adhesive may be any skin-friendly adhesive known perse, e.g. an adhesive comprising hydrocolloids or other moistureabsorbing constituents such as the adhesives disclosed in U.S. Pat. No.4,231,369 and in U.S. Pat. No. 4,367,732 comprising hydrocolloids. Adressing comprising a separate absorbing element may e.g. be of the typedisclosed in U.S. Pat. No. 5,051,259 or U.S. Pat. No. 5,714,225.

A water impervious layer or film may be of any suitable material knownper se for use in the preparation of wound dressings e.g. a foam, anon-woven layer or a polyurethane, polyethylene, polyester or polyamidefilm. A suitable material for use as a water impervious film is apolyurethane film such as the low friction film material is disclosed inU.S. Pat. No. 5,643,187.

A dressing of the invention preferably has bevelled edges in order toreduce the risk of “rolling-up” the edge of the dressing reducing thewear-time. A bevelling may be carried out discontinuously orcontinuously in a manner known per se e.g. as disclosed in EP patent No.0 264 299 or in U.S. Pat. No. 5,133,821.

The adhesive may be covered by a protective cover or release liner suchas siliconized paper. The protective cover is not present during the useof a dressing of the invention and is therefore not an essential part ofthe invention.

The dressing of the invention has mainly been described with referenceto wound dressings but it will be evident for the skilled in the artthat the invention is not limited to wound dressings. Thus, a medicaldressing of the invention may be in the form of a wound dressing or anostomy appliance or a dressing for covering an incision site in theskin.

The invention further relates to a method for preparing a medicaldressing in the form of a foam comprising a complex of silver and atransitional element of Group IV of the periodic system of elementswhich method comprises mixing the complex of silver and an element oftransition Group IV of the periodic system of elements with water and asurfactant, adding one or more prepolymer(s) during mixing, transformingthe resulting mixture into thin layer having a predetermined thickness,letting the resulting mixture foam and drying the resulting sheet at anelevated temperature. It is contemplated that such a foam system mayalso be produced directly from isocyanate and polyol(s).

Still further, the invention relates to a method of absorbing exudatefrom a wound or from an artificial orifice or opening such as the end ofan intestine or stoma protruding from the skin of a human body or theskin around a stoma or the area around an incision point for drainageand which method comprises

a) identifying the wound, stoma, fistula or drainage site of thepatient,

b) securing a medical dressing comprising a complex of silver and beingcapable of releasing antimicrobial silver ion activity, said complexcomprising silver and a transitional element of Group IV of the periodicsystem of elements to the patient's skin in such a manner that coversthe area of a wound or surrounds the area of the stoma, the fistula orthe drainage site.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention is now explained more in detail with reference to thebelow working Example which discloses preferred embodiments of theinvention and which is not to be considered as limiting the scope of theprotection set forth in the appended claims.

MATERIALS AND METHODS

Newborn Calf Serum, Gibco BRL (Lot. No.: 3033873D)

Sodium nitrate, Merck, analytical grade (Lot. No.: 259337-120)

Calcium Nitrate tetra hydrate, Merck, analytical grade (Lot. No.:93252-647)

Ion exchanged water (Conductivity 0.04 μS) from internal laboratorysupply

Silver nitrate standard 1000 mg/ml, KEBO lab. (Lot. No.: 19797.0500)

Hypol 2002 polyurethane prepolymer, Dow Chemicals

Pluronic 6200 PO-PE block copolymer, BASF

Silver Sodium Hydrogen Zirconium Phosphate available under the Tradename AlphaSan®, Milliken Chemicals

Acticoat Seven, a silver containing wound dressing from WestaimBiomedicals™ Atomic absorption spectrophotometer (Perkin Elmer 305)

A 0.5M sodium nitrate solution was prepared by dissolving 42.49 grams ofsodium nitrate in one litre of ion exchanged water during stirring.

A 0.5M calcium nitrate solution was prepared by dissolving 87.07 gramsof sodium nitrate in one litre of ion exchanged water during stirring.

Method for Measuring the Release of Silver:

The release of silver was determined by the following method.

Step A) Samples of the material to be tested were punched out in theform of discs having a diameter of 30 mm.

Step B) The sample was immersed in 50 ml of each of the test solutionsand stirring was started (T₀).

Step C) After stirring for 1, 5, and 24 hours, respectively, 5.0milliliters of release medium was sampled and replaced with 5.0milliliters of fresh medium.

Step D) Each sample was analysed using an atomic absorptionspectrophotometer and the content of Silver was calculated and presentedas a plot as a function of time. Each experiment was carried out intriplicate.

EXAMPLE Preparation of Antibacterial Foam Product According to theInvention.

A polyurethane foam sheet was produced by mixing Hypol 2002 (20 grams),Pluronic 6200 (0.2 grams), water (20 grams), silver sodium hydrogenzirconium phosphate (3 grams) by first mixing the water, silver compoundand Pluronic and then adding this mixture to the Hypol during mixing.While the mixture still was fluid it was transformed into thin layer bypouring the mixture onto a glass plate, placing a siliconised releasepaper on the mixture and adjusting the thickness to 2 mm using guidingbars and a doctor roll, allowing the mixture to foam for severalminutes. When the material was foamed, the foam sheet was dried in a dryair oven at 130° C. The final foamed sheet had a thickness of 4.5 mm anda content of silver of 9200 mg per square meter of foam (0.92 mgsilver/cm²).

The release of silver from the product when contacted with differentsolutions was determined as milligrammes of silver released. The resultsare presented in the below Table 1 and in FIG. 1.

TABLE 1 Concentration (μg/ml) Release Medium 1 hour 5 hours 24 hoursNewborn calf serum 5.22 15.74 43.38 Ion exchanged water 0 0 0 Calciumnitrate 0 0 0 Sodium nitrate 13.76 32.24 57.64

As appears from Table 1 and FIG. 1, no silver was released when incontact with ion exchanged water or calcium nitrate solution whereas arapid release of silver ions takes place when in contact with monovalentcationic solutions. The highest release of silver was seen when incontact with 0.5M sodium nitrate solution and newborn calf serum whichmedia both contain monovalent cations.

COMPARATIVE EXAMPLE

The release of silver from Acticoat Seven was determined using the sameprocedure as above and the results are presented in the below Table 2and in FIG. 2.

TABLE 2 Concentration (μg/ml) Release medium 1 hour 5 hours 24 hoursNewborn calf serum 9.75 25.04 38.81 Ion exchanged water 12.29 28.7551.83 Calcium nitrate 35.63 67.43 75.99 Sodium nitrate 21.45 44.18 61.39

As appears from Table 2 and FIG. 2, silver is released in ion-exchangedwater, calcium nitrate solution, sodium nitrate solution, and in newborncalf serum.

Thus, the foam of the invention is superior to the known product withrespect to controlling the release of silver ions in that no activity isreleased when contacted with ion exchanged water whereas a much higherrelease is observed when in contact with monovalent cations which aree.g. present in new-born calf serum.

1. A medical dressing comprising: a) an antimicrobial complex consistingessentially of: 1) silver ion; 2) a transitional element of Group IV ofthe Periodic System of Elements selected from the group consisting ofzirconium, titanium and hafnium; 3) at least one cation selected fromthe group consisting of lithium, sodium and potassium; 4) phosphate; and5) hydrogen; b) at least one absorbing element selected from the groupconsisting of an absorbing foam; said absorbing element being a separateelement in said dressing; c) said antimicrobial complex being mixedwithin said absorbing element such that the concentration of silver ionis between about 0.01 to 30 mg silver/cm² wound dressing; d) wherein thesilver ion in said antimicrobial complex mixed within said absorbingelement, is only capable of being released from said absorbing elementwhen placed in contact with wound exudate or fluid containing monovalentcations; and e) and wherein the silver ion is released in an effectiveamount to exhibit antiseptic activity in a wound when placed in contactwith a wound secreting exudate or fluid containing monovalent cations.2. A medical dressing as claimed in claim 1, wherein the silver ion isin the form of complex with zirconium.
 3. A medical dressing as claimedin claim 2, wherein the silver ion is in the form of a silver sodiumhydrogen zirconium phosphate complex.
 4. A medical dressing as claimedin claim 1, wherein said dressing comprises a polyurethane foam layerforming at least a part of the skin contacting surface of the dressing.5. A medical dressing as claimed in claim 1, wherein the skin contactingsurface comprises an area having a skin friendly adhesive.
 6. A medicaldressing as claimed in claim 1, wherein said dressing is in the form ofa wound dressing or an ostomy appliance or a dressing for covering anincision site in the skin.
 7. A method of absorbing exudate from a woundor from an artificial orifice or opening and treating the same withsilver ions, which method comprises the steps of: a) identifying thewound, artificial orifice or opening of the patient; and b) securing amedical dressing comprising the dressing of claim 1 in such a mannerthat said dressing covers the area of a wound or surrounds the area ofthe artificial orifice or opening.
 8. The method of absorbing exudate ofclaim 7, wherein said artificial orifice or opening is the end of anintestine or stoma protruding from the skin of a human body, or the skinaround a stoma, or the area around an incision point for drainage.
 9. Amedical dressing comprising: a) an antimicrobial complex consistingessentially of: 1) silver ion; 2) a transitional element of Group IV ofthe Periodic System of Elements selected from the group consisting ofzirconium, titanium and hafnium; 3) at least one cation selected fromthe group consisting of lithium, sodium and potassium; and 4) phosphate;and 5) hydrogen; b) at least one absorbing element consisting ofalginates, and said absorbing element being homogeneously distributed inthe dressing; c) said antimicrobial complex being mixed within saidabsorbing element such that the concentration of silver ion is betweenabout 0.01 to 30 rag silver/cm² wound dressing; d) wherein the silverion in said antimicrobial complex mixed within said absorbing element isonly capable of being released from said absorbing element when placedin contact with wound exudate or fluid containing monovalent cations;and e) wherein the silver ion is released in an effective amount toexhibit antiseptic activity in a wound when placed in contact with awound secreting exudate or fluid containing monovalent cations.
 10. Amedical dressing as claimed in claim 9, wherein the silver ion is in theform of complex with zirconium.
 11. A medical dressing as claimed inclaim 10, wherein the silver ion is in the form of a silver sodiumhydrogen zirconium phosphate complex.
 12. A medical dressing as claimedin claim 9, wherein said dressing comprises a polyurethane foam layerforming at least a part of the skin contacting surface of the dressing.13. A medical dressing as claimed in claim 9, wherein the skincontacting surface comprises an area having a skin friendly adhesive.14. A medical dressing as claimed in claim 9, wherein said dressing isin the form of a wound dressing or an ostomy appliance or a dressing forcovering an incision site in the skin.
 15. A methods of absorbingexudate from a wound or from an artificial orifice or opening andtreating the same with silver ions, which method comprises the steps of:a) identifying the wound, artificial orifice or opening of the patient;and b) securing a medical dressing comprising the dressing of claim 9 insuch a manner that said dressing covers the area of a wound or surroundsthe area of the artificial orifice or opening.
 16. The method ofabsorbing exudates of claim 15, wherein said artificial orifice oropening is the end of an intestine or stoma protruding from the skin ofa human body, or the skin around a stoma, or the area around an incisionpoint for drainage.
 17. A medical dressing comprising: a) anantimicrobial complex consisting essentially of: 1) silver ion; 2) atransitional element of Group IV of the Periodic System of Elementsselected from the group consisting of zirconium, titanium and hafnium;3) at least one cation selected from the group consisting of lithium,sodium and potassium; 4) phosphate; and 5) hydrogen; b) at least oneabsorbing element consisting of alginates, said absorbing element beinga separate element in said dressing; c) said antimicrobial complex beingmixed within said absorbing element such that the concentration ofsilver ion is between about 0.01 to 30 mg silver/cm² wound dressing; d)wherein the silver ion in said antimicrobial complex mixed within saidabsorbing element is only capable of being released from said absorbingelement when placed in contact with wound exudate or fluid containingmonovalent cations; and e) wherein the silver ion is released in aneffective amount to exhibit antiseptic activity in a wound when placedin contact with a wound secreting exudate or fluid containing monovalentcations.
 18. A medical dressing as claimed in claim 17, wherein thesilver ion is in the form of complex with zirconium.
 19. A medicaldressing as claimed in claim 18, wherein the silver ion is in the formof a silver sodium hydrogen zirconium phosphate complex.
 20. A medicaldressing as claimed in claim 17, wherein said dressing comprises apolyurethane foam layer forming at least a part of the skin contactingsurface of the dressing.
 21. A medical dressing as claimed in claim 17,wherein the skin contacting surface comprises an area having a skinfriendly adhesive.
 22. A medical dressing as claimed in claim 17,wherein said dressing is in the form of a wound dressing or an ostomyappliance or a dressing for covering an incision site in the skin.
 23. Amethod of absorbing exudate from a wound or from an artificial orificeor opening and treating the same with silver ions, which methodcomprises the steps of: a) identifying the wound, artificial orifice oropening of the patient; and b) securing a medical dressing comprisingthe dressing of claim 17 in such a manner that said dressing covers thearea of a wound or surrounds the area of the artificial orifice oropening.
 24. The method of absorbing exudates of claim 23, wherein saidartificial orifice or opening is the end of an intestine or stomaprotruding from the skin of a human body, or the skin around a stoma, orthe area around an incision point for drainage.
 25. A medical dressingas claimed in claim 1, wherein the absorbing foam is polyurethane foam.